John A. Curtin, Ph.D., Jane Fridlyand, Ph.D., Toshiro Kageshita, M.D., Hetal N. Patel, M.S., Klaus J. Busam, M.D., Heinz Kutzner, M.D., Kwang-Hyun Cho, M.D., Setsuya Aiba, M.D., Ph.D., Eva-Bettina Bröcker, M.D., Philip E. LeBoit, M.D., Dan Pinkel, Ph.D., and Boris C. Bastian, M.D.
Background Exposure to ultraviolet light is a major causativefactor in melanoma, although the relationship between risk andexposure is complex. We hypothesized that the clinical heterogeneityis explained by genetically distinct types of melanoma withdifferent susceptibility to ultraviolet light.
Methods We compared genome-wide alterations in the number ofcopies of DNA and mutational status of BRAF and N-RAS in 126melanomas from four groups in which the degree of exposure toultraviolet light differs: 30 melanomas from skin with chronicsun-induced damage and 40 melanomas from skin without such damage;36 melanomas from palms, soles, and subungual (acral) sites;and 20 mucosal melanomas.
Results We found significant differences in the frequenciesof regional changes in the number of copies of DNA and mutationfrequencies in BRAF among the four groups of melanomas. Samplescould be correctly classified into the four groups with 70 percentaccuracy on the basis of the changes in the number of copiesof genomic DNA. In two-way comparisons, melanomas arising onskin with signs of chronic sun-induced damage and skin withoutsuch signs could be correctly classified with 84 percent accuracy.Acral melanoma could be distinguished from mucosal melanomawith 89 percent accuracy. Eighty-one percent of melanomas onskin without chronic sun-induced damage had mutations in BRAFor N-RAS; the majority of melanomas in the other groups hadmutations in neither gene. Melanomas with wild-type BRAF orN-RAS frequently had increases in the number of copies of thegenes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1),downstream components of the RAS–BRAF pathway.
Conclusions The genetic alterations identified in melanomasat different sites and with different levels of sun exposureindicate that there are distinct genetic pathways in the developmentof melanoma and implicate CDK4 and CCND1 as independent oncogenesin melanomas without mutations in BRAF or N-RAS.
Source Information
From the Comprehensive Cancer Center (J.A.C., J.F., H.N.P., D.P., B.C.B.) and the Departments of Epidemiology and Biostatistics (J.F.) and Dermatology and Pathology (P.E.L., B.C.B.), University of California, San Francisco, San Francisco; the Department of Dermatology, Kumamoto University School of Medicine, Kumamoto, Japan (T.K.); the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York (K.J.B.); DermPath, Friedrichshafen, Germany (H.K.); the Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea (K.-H.C.); the Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan (S.A.); and the Department of Dermatology, University of Würzburg, Würzburg, Germany (E.-B.B.).
Address reprint requests to Dr. Bastian at UCSF Cancer Center, Box 0808, San Francisco, CA 94143-0808, or at bastian{at}cc.ucsf.edu.
Freedberg, D. E., Rigas, S. H., Russak, J., Gai, W., Kaplow, M., Osman, I., Turner, F., Randerson-Moor, J. A., Houghton, A., Busam, K., Timothy Bishop, D., Bastian, B. C., Newton-Bishop, J. A., Polsky, D.
(2008). Frequent p16-Independent Inactivation of p14ARF in Human Melanoma. JNCI J Natl Cancer Inst
100: 784-795
[Abstract][Full Text]
Lo, R. S., Witte, O. N.
(2008). Transforming Growth Factor-{beta} Activation Promotes Genetic Context-Dependent Invasion of Immortalized Melanocytes. Cancer Res.
68: 4248-4257
[Abstract][Full Text]
Greshock, J., Cheng, J., Rusnak, D., Martin, A. M., Wooster, R., Gilmer, T., Lee, K., Weber, B. L., Zaks, T.
(2008). Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines. Molecular Cancer Therapeutics
7: 935-943
[Abstract][Full Text]
Tucker, M. A.
(2008). Is Sunlight Important to Melanoma Causation?. Cancer Epidemiol. Biomarkers Prev.
17: 467-468
[Full Text]
Meyskens, F. L. Jr., Berwick, M.
(2008). UV or Not UV: Metals Are The Answer. Cancer Epidemiol. Biomarkers Prev.
17: 268-270
[Full Text]
Hoek, K. S., Eichhoff, O. M., Schlegel, N. C., Dobbeling, U., Kobert, N., Schaerer, L., Hemmi, S., Dummer, R.
(2008). In vivo Switching of Human Melanoma Cells between Proliferative and Invasive States. Cancer Res.
68: 650-656
[Abstract][Full Text]
Lin, W. M., Baker, A. C., Beroukhim, R., Winckler, W., Feng, W., Marmion, J. M., Laine, E., Greulich, H., Tseng, H., Gates, C., Hodi, F. S., Dranoff, G., Sellers, W. R., Thomas, R. K., Meyerson, M., Golub, T. R., Dummer, R., Herlyn, M., Getz, G., Garraway, L. A.
(2008). Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma. Cancer Res.
68: 664-673
[Abstract][Full Text]
Vallacchi, V., Daniotti, M., Ratti, F., Di Stasi, D., Deho, P., De Filippo, A., Tragni, G., Balsari, A., Carbone, A., Rivoltini, L., Parmiani, G., Lazar, N., Perbal, B., Rodolfo, M.
(2008). CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma. Cancer Res.
68: 715-723
[Abstract][Full Text]
Liu, S., Wang, H., Currie, B. M., Molinolo, A., Leung, H. J., Moayeri, M., Basile, J. R., Alfano, R. W., Gutkind, J. S., Frankel, A. E., Bugge, T. H., Leppla, S. H.
(2008). Matrix Metalloproteinase-activated Anthrax Lethal Toxin Demonstrates High Potency in Targeting Tumor Vasculature. J. Biol. Chem.
283: 529-540
[Abstract][Full Text]
Zell, J. A., Cinar, P., Mobasher, M., Ziogas, A., Meyskens, F. L. Jr, Anton-Culver, H.
(2008). Survival for Patients With Invasive Cutaneous Melanoma Among Ethnic Groups: The Effects of Socioeconomic Status and Treatment. JCO
26: 66-75
[Abstract][Full Text]
Sabatino, M., Zhao, Y., Voiculescu, S., Monaco, A., Robbins, P., Karai, L., Nickoloff, B. J., Maio, M., Selleri, S., Marincola, F. M., Wang, E.
(2008). Conservation of Genetic Alterations in Recurrent Melanoma Supports the Melanoma Stem Cell Hypothesis. Cancer Res.
68: 122-131
[Abstract][Full Text]
Liao, Y.-H., Hsu, S.-M., Huang, P.-H.
(2007). ARMS Depletion Facilitates UV Irradiation Induced Apoptotic Cell Death in Melanoma. Cancer Res.
67: 11547-11556
[Abstract][Full Text]
Solit, D. B., Santos, E., Pratilas, C. A., Lobo, J., Moroz, M., Cai, S., Blasberg, R., Sebolt-Leopold, J., Larson, S., Rosen, N.
(2007). 3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition. Cancer Res.
67: 11463-11469
[Abstract][Full Text]
Delmas, V., Beermann, F., Martinozzi, S., Carreira, S., Ackermann, J., Kumasaka, M., Denat, L., Goodall, J., Luciani, F., Viros, A., Demirkan, N., Bastian, B. C., Goding, C. R., Larue, L.
(2007). beta-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev.
21: 2923-2935
[Abstract][Full Text]
Abbas, S., Bhoumik, A., Dahl, R., Vasile, S., Krajewski, S., Cosford, N. D.P., Ronai, Z. A.
(2007). Preclinical Studies of Celastrol and Acetyl Isogambogic Acid in Melanoma. Clin. Cancer Res.
13: 6769-6778
[Abstract][Full Text]
McDermott, D. F., Atkins, M. B.
(2007). More Support for the Judicious Use of High-Dose Interleukin-2 in Patients With Advanced Melanoma. JCO
25: 3791-3793
[Full Text]
Thomas, N. E., Edmiston, S. N., Alexander, A., Millikan, R. C., Groben, P. A., Hao, H., Tolbert, D., Berwick, M., Busam, K., Begg, C. B., Mattingly, D., Ollila, D. W., Tse, C. K., Hummer, A., Lee-Taylor, J., Conway, K.
(2007). Number of Nevi and Early-Life Ambient UV Exposure Are Associated with BRAF-Mutant Melanoma. Cancer Epidemiol. Biomarkers Prev.
16: 991-997
[Abstract][Full Text]
Fecher, L. A., Cummings, S. D., Keefe, M. J., Alani, R. M.
(2007). Toward a Molecular Classification of Melanoma. JCO
25: 1606-1620
[Abstract][Full Text]
Greshock, J., Nathanson, K., Martin, A.-M., Zhang, L., Coukos, G., Weber, B. L., Zaks, T. Z.
(2007). Cancer Cell Lines as Genetic Models of Their Parent Histology: Analyses Based on Array Comparative Genomic Hybridization. Cancer Res.
67: 3594-3600
[Abstract][Full Text]
Stark, M., Hayward, N.
(2007). Genome-Wide Loss of Heterozygosity and Copy Number Analysis in Melanoma Using High-Density Single-Nucleotide Polymorphism Arrays. Cancer Res.
67: 2632-2642
[Abstract][Full Text]
Becker, J. C., Brocker, E. B., Schadendorf, D., Ugurel, S.
(2007). Imatinib in Melanoma: A Selective Treatment Option Based on KIT Mutation Status?. JCO
25: e9-e9
[Full Text]
Shields, J. M., Thomas, N. E., Cregger, M., Berger, A. J., Leslie, M., Torrice, C., Hao, H., Penland, S., Arbiser, J., Scott, G., Zhou, T., Bar-Eli, M., Bear, J. E., Der, C. J., Kaufmann, W. K., Rimm, D. L., Sharpless, N. E.
(2007). Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma. Cancer Res.
67: 1502-1512
[Abstract][Full Text]
Hollestelle, A., Elstrodt, F., Nagel, J. H.A., Kallemeijn, W. W., Schutte, M.
(2007). Phosphatidylinositol-3-OH Kinase or RAS Pathway Mutations in Human Breast Cancer Cell Lines. Mol Cancer Res
5: 195-201
[Abstract][Full Text]
Climent, J., Dimitrow, P., Fridlyand, J., Palacios, J., Siebert, R., Albertson, D. G., Gray, J. W., Pinkel, D., Lluch, A., Martinez-Climent, J. A.
(2007). Deletion of Chromosome 11q Predicts Response to Anthracycline-Based Chemotherapy in Early Breast Cancer. Cancer Res.
67: 818-826
[Abstract][Full Text]
Muthusamy, V., Duraisamy, S., Bradbury, C. M., Hobbs, C., Curley, D. P., Nelson, B., Bosenberg, M.
(2006). Epigenetic Silencing of Novel Tumor Suppressors in Malignant Melanoma. Cancer Res.
66: 11187-11193
[Abstract][Full Text]
Verhaegen, M., Bauer, J. A., Martin de la Vega, C., Wang, G., Wolter, K. G., Brenner, J. C., Nikolovska-Coleska, Z., Bengtson, A., Nair, R., Elder, J. T., Van Brocklin, M., Carey, T. E., Bradford, C. R., Wang, S., Soengas, M. S.
(2006). A Novel BH3 Mimetic Reveals a Mitogen-Activated Protein Kinase-Dependent Mechanism of Melanoma Cell Death Controlled by p53 and Reactive Oxygen Species. Cancer Res.
66: 11348-11359
[Abstract][Full Text]
Lipsker, D.
(2006). Growth Rate, Early Detection, and Prevention of Melanoma: Melanoma Epidemiology Revisited and Future Challenges. Arch Dermatol
142: 1638-1640
[Full Text]
Becker, D., Mihm, M. C., Hewitt, S. M., Sondak, V. K., Fountain, J. W., Thurin, M.
(2006). Markers and Tissue Resources for Melanoma: Meeting Report.. Cancer Res.
66: 10652-10657
[Abstract][Full Text]
Prieto, V. G., Mourad-Zeidan, A. A., Melnikova, V., Johnson, M. M., Lopez, A., Diwan, A. H., Lazar, A. J.F., Shen, S. S., Zhang, P. S., Reed, J. A., Gershenwald, J. E., Raz, A., Bar-Eli, M.
(2006). Galectin-3 Expression Is Associated with Tumor Progression and Pattern of Sun Exposure in Melanoma.. Clin. Cancer Res.
12: 6709-6715
[Abstract][Full Text]
Lopez-Knowles, E., Hernandez, S., Kogevinas, M., Lloreta, J., Amoros, A., Tardon, A., Carrato, A., Kishore, S., Serra, C., Malats, N., Real, F. X., on behalf of the EPICURO Study Investigators,
(2006). The p53 Pathway and Outcome among Patients with T1G3 Bladder Tumors.. Clin. Cancer Res.
12: 6029-6036
[Abstract][Full Text]
Cormier, J. N., Xing, Y., Ding, M., Lee, J. E., Mansfield, P. F., Gershenwald, J. E., Ross, M. I., Du, X. L.
(2006). Ethnic differences among patients with cutaneous melanoma.. Arch Intern Med
166: 1907-1914
[Abstract][Full Text]
Hwu, P., Bedikian, A. Y., Grimm, E. A.
(2006). Challenges of chemosensitivity testing.. Clin. Cancer Res.
12: 5258-5259
[Full Text]
Mitchell, D.
(2006). Revisiting the photochemistry of solar UVA in human skin. Proc. Natl. Acad. Sci. USA
103: 13567-13568
[Full Text]
Curtin, J. A., Busam, K., Pinkel, D., Bastian, B. C.
(2006). Somatic Activation of KIT in Distinct Subtypes of Melanoma. JCO
24: 4340-4346
[Abstract][Full Text]
Matsukuma, S., Yoshihara, M., Kasai, F., Kato, A., Yoshida, A., Akaike, M., Kobayashi, O., Nakayama, H., Sakuma, Y., Yoshida, T., Kameda, Y., Tsuchiya, E., Miyagi, Y.
(2006). Rapid and Simple Detection of Hot Spot Point Mutations of Epidermal Growth Factor Receptor, BRAF, and NRAS in Cancers Using the Loop-Hybrid Mobility Shift Assay. J. Mol. Diagn.
8: 504-512
[Abstract][Full Text]
Packer, L., Pavey, S., Parker, A., Stark, M., Johansson, P., Clarke, B., Pollock, P., Ringner, M., Hayward, N.
(2006). Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN. Carcinogenesis
27: 1778-1786
[Abstract][Full Text]
Gao, L., Feng, Y., Bowers, R., Becker-Hapak, M., Gardner, J., Council, L., Linette, G., Zhao, H., Cornelius, L. A.
(2006). Ras-Associated Protein-1 Regulates Extracellular Signal-Regulated Kinase Activation and Migration in Melanoma Cells: Two Processes Important to Melanoma Tumorigenesis and Metastasis. Cancer Res.
66: 7880-7888
[Abstract][Full Text]
Chin, L., Garraway, L. A., Fisher, D. E.
(2006). Malignant melanoma: genetics and therapeutics in the genomic era.. Genes Dev.
20: 2149-2182
[Abstract][Full Text]
Tormo, D., Ferrer, A., Gaffal, E., Wenzel, J., Basner-Tschakarjan, E., Steitz, J., Heukamp, L. C., Gutgemann, I., Buettner, R., Malumbres, M., Barbacid, M., Merlino, G., Tuting, T.
(2006). Rapid Growth of Invasive Metastatic Melanoma in Carcinogen-Treated Hepatocyte Growth Factor/Scatter Factor-Transgenic Mice Carrying an Oncogenic CDK4 Mutation. Am. J. Pathol.
169: 665-672
[Abstract][Full Text]
Perry, B. N., Cohen, C., Govindarajan, B., Cotsonis, G., Arbiser, J. L.
(2006). Wilms tumor 1 expression present in most melanomas but nearly absent in nevi.. Arch Dermatol
142: 1031-1034
[Abstract][Full Text]
Saldanha, G., Potter, L., DaForno, P., Pringle, J. H.
(2006). Cutaneous Melanoma Subtypes Show Different BRAF and NRAS Mutation Frequencies. Clin. Cancer Res.
12: 4499-4505
[Abstract][Full Text]
Landi, M. T., Bauer, J., Pfeiffer, R. M., Elder, D. E., Hulley, B., Minghetti, P., Calista, D., Kanetsky, P. A., Pinkel, D., Bastian, B. C.
(2006). MC1R Germline Variants Confer Risk for BRAF-Mutant Melanoma. Science
313: 521-522
[Abstract][Full Text]
Miller, A. J., Mihm, M. C. Jr.
(2006). Melanoma.. NEJM
355: 51-65
[Full Text]
Whiteman, D. C., Stickley, M., Watt, P., Hughes, M. C., Davis, M. B., Green, A. C.
(2006). Anatomic Site, Sun Exposure, and Risk of Cutaneous Melanoma. JCO
24: 3172-3177
[Abstract][Full Text]
Petti, C., Molla, A., Vegetti, C., Ferrone, S., Anichini, A., Sensi, M.
(2006). Coexpression of NRASQ61R and BRAFV600E in Human Melanoma Cells Activates Senescence and Increases Susceptibility to Cell-Mediated Cytotoxicity.. Cancer Res.
66: 6503-6511
[Abstract][Full Text]
Mirmohammadsadegh, A., Marini, A., Nambiar, S., Hassan, M., Tannapfel, A., Ruzicka, T., Hengge, U. R.
(2006). Epigenetic Silencing of the PTEN Gene in Melanoma.. Cancer Res.
66: 6546-6552
[Abstract][Full Text]
Desai, A., Krathen, R., Orengo, I., Medrano, E. E.
(2006). The age of skin cancers.. Sci Aging Knowl Environ
2006: pe13-pe13
[Abstract][Full Text]
Elder, D. E.
(2006). Pathology of melanoma.. Clin. Cancer Res.
12: 2308s-2311s
[Abstract][Full Text]
Koon, H., Atkins, M.
(2006). Autoimmunity and Immunotherapy for Cancer. NEJM
354: 758-760
[Full Text]
Goding, C., Meyskens, F. L. Jr.
(2006). Microphthalmic-Associated Transcription Factor Integrates Melanocyte Biology and Melanoma Progression. Clin. Cancer Res.
12: 1069-1073
[Full Text]
Previous
